A piperidine compound (II) represented by the formula (II): ##STR2##
wherein A represents a lower alkyl group, hydroxyl group, a lower alkoxy group, amino group, a lower alkylamino group, phenyl group or a lower alkyl-substituted phenyl group, PA1 wherein * represents an asymmetric carbon, which has an absolute configuration of (S). PA1 wherein R represents a lower alkyl group such as methyl group, ethyl group, etc., and W represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy group, p-toluenesulfonyloxy group, etc., to obtain (S)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine butanoic acid ester represented by the formula (VI): PA1 wherein R and * have the same meaning as defined above, hydrolyzing the resulting compound; and reacting the hydrolyzed compound with benzenesulfonic acid or benzoic acid to form a salt. PA1 wherein HX represents benzenesulfonic acid or benzoic acid, and * has the same meaning as defined above, (hereinafter referred to as a salt-forming reaction). PA1 wherein W represents a leaving group, including a halogen atom such as chlorine atom, bromine atom, iodine atom, etc.; or a reactive ester group such as methanesulfonyloxy group, p-toluenesulfonyloxy group, etc., and R represents a lower alkyl group such as methyl group, ethyl group, etc., and * has the same meaning as defined above. PA1 wherein * represents an asymmetric carbon, (.+-.)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine which is a starting compound and represented by the formula (III) is previously optically resolved and the resulting optically active (S)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine represented by the formula (IV) is used as a synthetic intermediate. PA1 wherein Y represents a hydrogen atom or a halogen atom; PA1 Z represents a lower alkoxy group; and * represents an asymmetric carbon, PA1 wherein * has the same meanings as defined above. PA1 (S)-isomer PA1 (R)-isomer about 7 to 10 minutes PA1 (S)-isomer about 13 to 15 minutes
or a salt thereof described in Japanese Provisional Patent Publication No. 25465/1990 has characteristics that a secondary effect such as stimulation or suppression on the central nerves, which often appears in the conventional antihistaminic compound, can be reduced as little as possible, and is expected to be a medicine for therapeutic treatment of allergic skin diseases such as a nettle rash, eczema, dermatitis and the like, allergic rhinitis, sneeze, mucus, cough due to respiratory inflammation such as cold and the like, and bronchial asthma.
For producing the piperidine compound (II) effectively as a more preferred optical isomer for a medicine, it is desired to use the optically resolved product as a starting material by optically resolving an intermediate. However, this piperidine compound (II) has one asymmetric carbon atom but the method of isolating its optically active isomer from the racemic mixture has not been known as of today.
It has been generally known that optical isomers show different pharmacological activity or safety and there are also differences in the metabolic rates and the protein binding ratios therebetween (Pharmacia, 25 (4), pp. 311-336, 1989). Accordingly, for providing a medicine, a pharmaceutically preferable optical isomer with high optical purity is required. Also, in order to secure high quality of said optical isomer as a medicine, it is desirable that the isomer has superior properties in physicochemical stability.
The present inventors have studied intensively to solve the above problems. As the result, they have found that a benzenesulfonic acid salt or a benzoic acid salt of optically active (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid represented by the following formula (I) has excellent stability which is preferred as a medicine whereby accomplished the present invention.